Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there are a limited number of studies of longitudinal brain changes in individuals without dementia. We are performing serial magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease (AD). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. During the last year, we added PET imaging studies of amyloid distribution in the brain to our ongoing neuroimaging study to enhance the identification of preclinical AD. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic risk factors and the effects of sex steroid and other hormones. We are performing studies of the effects of estrogen and androgenic hormones on cognition and the brain in older women and men, respectively. Through the Women's Health Initiative Study of Cognitive Aging (WHISCA), we are continuing cognitive follow-up through an ancillary study of specific cognitive abilities and affect in the large randomized trial of hormone therapy in the Women's Health Initiative.[unreadable] [unreadable] We continued the development and validation of new tools for processing images for longitudinal studies. We validated our approach for analysis of structural MRI data and developed an approach for parcellation of the brain into volumes of interest that can be applied to large imaging databases. We have published reports delineating longitudinal age-changes in gray and white matter, as well as cerebrospinal volumes, in older individuals without dementia. We have demonstrated longitudinal tissue loss even in very healthy elderly and found that the rate of tissue loss was greater in individuals who had some health problems. Our longitudinal analysis of gray matter revealed a regional pattern of tissue loss, whereas white matter changes were more widespread. In addition,a recent publication of the analysis of the geometry of specific cortical regions revealed age differences and age changes in the sulcal regions of older adults. Our recent emphasis has been on the processing of additional follow-up MRI and PET data, emphasizing the analysis of the PET data while the next wave of MRI follow-ups are performed. The PET findings indicate cross-sectional and longitudinal effects of age, with decreased blood flow in specific regions in older compared with younger individuals and specific patterns of associations between cognition and regional cerebral blood flow. We have also delineated the unique patterns of brain activation characteristic of different components of memory processing in elderly adults.[unreadable] [unreadable] Our findings of specific regions of increased vulnerability to the effects of age have guided our development of specific probes for examination of cognitive and brain changes in the elderly. We have published studies of age differences in spatial navigation using computer-based virtual environments and more recently, the neurobiological substrates of these age differences using functional magnetic resonance imaging to show age differences in brain activation during virtual navigation performance. In addition, we previously demonstrated age differences in prefrontal functioning, showing differential effects of age on orbital frontal and dorsolateral prefrontal functions. We also completed and published a functional magnetic resonance imaging study of age differences in orbital frontal aging using tasks that differentially activate mesial versus lateral orbital frontal functioning. These findings showed the expected frontal activations in the young but not older subjects and indicated compensatory activations in more posterior regions in older individuals. [unreadable] [unreadable] Our studies of hormones as modulators of cognitive and brain aging also continue. We demonstrated positive associations between an index of free testosterone and memory and attentional functions in older men. Moreover, we reported that higher free (but not total) testosterone was associated with a reduced risk for Alzheimer's Disease. More recently, we reported that free testosterone was associated with increased regional cerebral blood flow in cingulate, temporal and prefrontal regions of older men in our longitudinal neuroimaging sample.[unreadable] [unreadable] Through the WHISCA study, we investigated the effects of combination estrogen plus progestin (E + P) treatment versus placebo on cognition and affect in older postmenopausal women in the E + P arm of the WHI hormone treatment trials. We examined 1416 women with up to 3 annual assessments prior to termination of study medications in the combination E + P arm of the main WHI trial due to an adverse risk profile. We reported significant decrements in verbal memory performance over time and a trend to increased figural memory performance over time in women who were taking E + P versus placebo, but these treatment effects were only evident after more than 3 years of treatment. We also found in an associational analysis that alcohol use was associated with better cognitive performance in the WHISCA sample. Data analysis is continuing for the estrogen only arm of the WHI trials. Cognitive assessments of WHISCA volunteers are continuing despite termination of study pills and will provide information on the effects of discontinuation of treatment and the long-term effects of hormone therapy, including whether the modest on-trial effects of study drugs endure post-trial. These studies will contribute to our understanding of the effects of steroid hormones on age-related cognitive changes in the elderly.